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Purpose: Cancer immune therapy has revolutionized patient outcome for the small mCRC subgroup with highly immunogenic disease. The majority of mCRC cases, however, are MSS with inherently low susceptibility to immune therapy. In our ongoing METIMMOX study (NCT03388190), MSS-mCRC patients are randomized to oxaliplatin-based immunogenic chemotherapy followed by ICI (experimental study arm) or the oxaliplatin-based standard-of-care (control arm). A subgroup of experimental arm patients has obtained durable major partial or complete responses. Such remarkable outcomes call for biomarkers that may help identifying MSS-mCRC patients who will benefit from such sequential therapy. Experimental procedures: Study enrollment began August 2018. Patients with unresectable, previously untreated MSS-mCRC have been randomized to the Nordic FLOX regimen (standard-of-care) or repeat sequential 2 FLOX cycles and 2 cycles of nivolumab (240 mg Q2W). At analysis October 2020, 48 patients were evaluable for progression-free survival (PFS). Serum collected at baseline and after the first 2 FLOX and 2 nivolumab cycles were analyzed for 42 immune factors with the Luminex multiplex immunoassay. The Significance Analysis for Microarrays method was applied to select the most significant proteins. Diffusion-weighted magnetic resonance imaging (DW-MRI) of the liver was performed at baseline and after the first 2 FLOX cycles. Using a b-value of 1000 s/mm2, the intensity ratio of a representative metastatic lesion relative to normal parenchymal tissue in the liver was calculated at each recording. Results: At this early time of analysis, with median follow-up of 8.6 (range, 1-21) months, median PFS for the entire groups of control and experimental arm patients was identical (6.4 and 6.6 months, respectively). We selected 13 experimental arm patients with long (median 13.6 months) or short (median 5.6 months) PFS for the serum protein analysis and 9 patients with liver DW-MRI. High serum CD40L levels (> median 47.6 ng/ml) at baseline or CD23 levels (> median 15.7 ng/ml) after the first 2 FLOX and 2 nivolumab cycles were both associated with improved PFS (p < 0.001 and p < 0.007; log-rank test). The baseline DW-MRI intensity of the peripheral hyperintense rim of the metastatic lesion (2.0- to 2.8-fold higher than the corresponding parenchymal value) diminished towards the parenchymal intensity (1.2- to 1.6-fold higher) after the first 2 FLOX cycles in patients with longer PFS than the median for all study patients. The rim intensity did not change in patients with short PFS. Conclusions: Three potential response markers in serum or at DW-MRI (one at baseline, one following the induction immunogenic chemotherapy, and one following the subsequent ICI) were identified for MSS-mCRC at this early time of the METIMMOX study conduct. Citation Format: Anne Hansen Ree, Sebastian Meltzer, Kine M. Bakke, Hanne M. Hamre, Christian Kersten, Eva Hofsli, Marianne Grønlie Guren, Halfdan Sorbye, Christin Johansen, Anne Negård, Kathrine Røe Redalen, Kjersti Flatmark. Immunogenic chemotherapy and immune checkpoint inhibition (ICI) in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC): Biomarkers indicative of durable treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 522.

Background and purpose We investigated how features relating to pelvic cavity anatomy and tumor hemodynamic factors may influence systemic failure in rectal cancer. Materials and methods Rectal cancer patients (207 women, 343 men), who had been prospectively enrolled onto six cohorts and given curative-intent therapy, were analyzed for the first metastatic event. In one of the cohorts, the diameter of the inferior mesenteric vein (IMV) was assessed on diagnostic abdominal computed tomography images (n = 113). Tumor volume (n = 193) and histologic response to neoadjuvant therapy (n = 445) were recorded from diagnostic magnetic resonance images and surgical specimens, respectively. Results More women than men developed lung metastasis (p = 0.037), while the opposite was the case for liver metastasis (p = 0.040). Wider IMV diameter correlated with larger tumor volume (r = 0.481, p < 0.001) and male sex (p < 0.001). Female sex was the only adverse prognostic factor for lung metastasis. When sex, tumor volume, and histologic response were taken into consideration, poor tumor response remained the only determinant for liver metastasis (p = 0.002). Conclusions In a diverse rectal cancer population given curative-intent treatment, women and men had different outcome with regard to the primary metastatic site. Tumor hemodynamic factors should be considered in rectal cancer risk stratification. (C) 2019 The Author(s). Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Background: In locally advanced rectal cancer (LARC), responses to preoperative treatment are highly heterogeneous and more accurate diagnostics are likely to enable more individualised treatment approaches with improved responses. We investigated the potential of diffusion-weighted magnetic resonance imaging (DW MRI), with quantification of the apparent diffusion coefficient (ADC) and perfusion fraction (F), as well as volumetry from T2-weighted (T2W) MRI, for prediction of therapeutic outcome. Material and methods: In 27 LARC patients receiving neoadjuvant chemotherapy (NACT) before chemoradiotherapy (CRT), T2W- and DW MRI were obtained before and after NACT. Tumour volumes were delineated in T2W MRI and ADCs and Fs were estimated from DW MRI using a simplified approach to the intravoxel incoherent motion (IVIM) model. Mean tumour values and histogram analysis of whole-tumour heterogeneity were correlated with histopathologic tumour regression grade (TRG) and 5-year progression-free survival (PFS). Results: At baseline, high tumour F predicted good tumour response (TRG1-2) (AUC = 0.79, p = 0.01), with a sensitivity of 69% and a specificity of 100%. The combination of F and tumour volume (Fpre/Vpre) gave the highest prediction of poor tumour response (AUC = 0.93, p

The liver is the most frequent metastatic site in colorectal cancer (CRC), and relevant orthotopic in vivo models are needed to study the efficacy of anticancer drugs in the metastatic setting. A challenge when utilizing such models is monitoring tumor growth during the experiments. In this study, experimental liver metastases were established in nude mice by splenic injection of the CRC cell lines HT29 and HCT116, and the mice were treated with the antiangiogenic drug aflibercept. Tumor growth was monitored using magnetic resonance imaging (MRI) and bioluminescence imaging (BLI). Aflibercept treatment was well tolerated and resulted in increased animal survival in HCT116, but not in HT29, while inhibited tumor growth was observed in both models. Treatment efficacy was monitored with high precision using MRI, while BLI detected small-volume disease with high sensitivity, but was less accurate in end-stage disease. Apparent diffusion coefficient (ADC) values obtained by diffusion weighted MRI (DW-MRI) were highly predictive of treatment response, with increased ADC corresponding well with areas of necrosis observed by histological evaluation of aflibercept-treated xenografts. The results showed that the efficacy of the antiangiogenic drug aflibercept varied between the two models, possibly reflecting unique growth patterns in the liver that may be representative of human disease. Non-invasive imaging, especially MRI and DW-MRI, can be used to effectively monitor tumor growth and treatment response in orthotopic liver metastasis models.